Graphical Abstract:

Abstract:

Cells of the monocyte/macrophage lineage are an important target for HIV-1 infection. They are often at
anatomical sites linked to HIV-1 transmission and are an important vehicle for disseminating HIV-1 throughout the body,
including the central nervous system. Monocytes do not support extensive productive HIV-1 replication, but they become
more susceptible to HIV-1infection as they differentiate into macrophages. The mechanisms guiding susceptibility of
HIV-1 replication in monocytes versus macrophages are not entirely clear. We determined whether endogenous activity of
β-catenin signaling impacts differential susceptibility of monocytes and monocyte-derived macrophages (MDMs) to
productive HIV-1 replication. We show that monocytes have an approximately 4-fold higher activity of β-catenin
signaling than MDMs. Inducing β-catenin in MDMs suppressed HIV-1 replication by 5-fold while inhibiting endogenous
β-catenin signaling in monocytes by transfecting with a dominant negative mutant for the downstream effector of β-
catenin (TCF-4) promoted productive HIV-1 replication by 6-fold. These findings indicate that β-catenin/TCF-4 is an
important pathway for restricted HIV-1 replication in monocytes and plays a significant role in potentiating HIV-1
replication as monocytes differentiate into macrophages. Targeting this pathway may provide a novel strategy to purge the
latent reservoir from monocytes/macrophages, especially in sanctuary sites for HIV-1 such as the central nervous system.

Abstract:Cells of the monocyte/macrophage lineage are an important target for HIV-1 infection. They are often at
anatomical sites linked to HIV-1 transmission and are an important vehicle for disseminating HIV-1 throughout the body,
including the central nervous system. Monocytes do not support extensive productive HIV-1 replication, but they become
more susceptible to HIV-1infection as they differentiate into macrophages. The mechanisms guiding susceptibility of
HIV-1 replication in monocytes versus macrophages are not entirely clear. We determined whether endogenous activity of
β-catenin signaling impacts differential susceptibility of monocytes and monocyte-derived macrophages (MDMs) to
productive HIV-1 replication. We show that monocytes have an approximately 4-fold higher activity of β-catenin
signaling than MDMs. Inducing β-catenin in MDMs suppressed HIV-1 replication by 5-fold while inhibiting endogenous
β-catenin signaling in monocytes by transfecting with a dominant negative mutant for the downstream effector of β-
catenin (TCF-4) promoted productive HIV-1 replication by 6-fold. These findings indicate that β-catenin/TCF-4 is an
important pathway for restricted HIV-1 replication in monocytes and plays a significant role in potentiating HIV-1
replication as monocytes differentiate into macrophages. Targeting this pathway may provide a novel strategy to purge the
latent reservoir from monocytes/macrophages, especially in sanctuary sites for HIV-1 such as the central nervous system.